A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Alan E Renton; Elisa Majounie; Adrian Waite; Javier Simón-Sánchez; Sara Rollinson; J. Raphael Gibbs; Jennifer C Schymick; Hannu Laaksovirta; John C van Swieten; Liisa Myllykangas; Hannu Kalimo; Anders Paetau; Yevgeniya Abramzon; Anne M Remes; Alice Kaganovich; Sonja W Scholz; Jamie Duckworth; Jinhui Ding; Daniel W Harmer; Dena G Hernandez; Janel O Johnson; Kin Mok; Mina Ryten; Danyah Trabzuni; Rita J Guerreiro; Richard W Orrell; James Neal; Alex Murray; Justin Pearson; Iris E Jansen; David Sondervan; Harro Seelaar; Derek Blake; Kate Young; Nicola Halliwell; Janis Bennion Callister; Greg Toulson; Anna Richardson; Alex Gerhard; Julie Snowden; David Mann; David Neary; Michael A Nalls; Terhi Peuralinna; Lilja Jansson; Veli-Matti Isoviita; Anna-Lotta Kaivorinne; Maarit Hölttä-Vuori; Elina Ikonen; Raimo Sulkava; Michael Benatar; Joanne Wuu; Adriano Chiò; Gabriella Restagno; Giuseppe Borghero; Mario Sabatelli; David Heckerman; Ekaterina Rogaeva; Lorne Zinman; Jeffrey D Rothstein; Michael Sendtner; Carsten Drepper; Evan E Eichler; Can Alkan; Ziedulla Abdullaev; Svetlana D Pack; Amalia Dutra; Evgenia Pak; John Hardy; Andrew Singleton; Nigel M Williams; Peter Heutink; Stuart Pickering-Brown; Huw R Morris; Pentti J Tienari; Bryan J Traynor

doi:10.1016/j.neuron.2011.09.010

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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Alan E Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J. Raphael Gibbs, Jennifer C Schymick, Hannu Laaksovirta, John C van Swieten, Liisa Myllykangas, …

Neuron (Cambridge, Mass.), Vol.72(2), pp.257-268

2011-10-20

DOI: https://doi.org/10.1016/j.neuron.2011.09.010

PMCID: PMC3200438

PMID: 21944779

Abstract

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date. ► A GGGGCC hexanucleotide repeat expansion causes chromosome 9p21 FTD/ALS ► The GGGGCC repeat expansion accounts for nearly half of familial ALS in Finland ► The GGGGCC repeat expansion accounts for more than 1/3 of familial ALS in Europe ► The repeat expansion is the most common cause of ALS and FTD identified to date

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 Amyotrophic Lateral Sclerosis
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Creators: Alan E Renton - Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Elisa Majounie - Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Adrian Waite - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Javier Simón-Sánchez - Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
Sara Rollinson - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
J. Raphael Gibbs - Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Jennifer C Schymick - Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Hannu Laaksovirta - Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland
John C van Swieten - Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
Liisa Myllykangas - Department of Pathology, Haartman Institute/HUSLAB, University of Helsinki and Folkhälsan Research Center (LM), Helsinki, FIN-02900, Finland
Hannu Kalimo - Department of Pathology, Haartman Institute/HUSLAB, University of Helsinki and Folkhälsan Research Center (LM), Helsinki, FIN-02900, Finland
Anders Paetau - Department of Pathology, Haartman Institute/HUSLAB, University of Helsinki and Folkhälsan Research Center (LM), Helsinki, FIN-02900, Finland
Yevgeniya Abramzon - Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Anne M Remes - Institute of Clinical Medicine, Neurology, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, FIN-90014, Finland
Alice Kaganovich - Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Sonja W Scholz - Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Jamie Duckworth - Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Jinhui Ding - Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Daniel W Harmer - Illumina Inc., Hayward, CA 94545, USA
Dena G Hernandez - Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Janel O Johnson - Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Kin Mok - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK
Mina Ryten - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK
Danyah Trabzuni - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK
Rita J Guerreiro - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK
Richard W Orrell - Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UK
James Neal - Department of Pathology, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Alex Murray - Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK
Justin Pearson - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Iris E Jansen - Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
David Sondervan - Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
Harro Seelaar - Department of Neurology, Erasmus MC - University Medical Center Rotterdam, 3015 CE, Rotterdam, The Netherlands
Derek Blake - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Kate Young - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
Nicola Halliwell - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
Janis Bennion Callister - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
Greg Toulson - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
Anna Richardson - Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK
Alex Gerhard - Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK
Julie Snowden - Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK
David Mann - Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK
David Neary - Neurodegeneration and Mental Health Research Group, Cerebral Function Unit, School of Community Based Medicine, University of Manchester, Manchester M6 8HD, UK
Michael A Nalls - Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Terhi Peuralinna - Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland
Lilja Jansson - Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland
Veli-Matti Isoviita - Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland
Anna-Lotta Kaivorinne - Institute of Clinical Medicine, Neurology, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, FIN-90014, Finland
Maarit Hölttä-Vuori - Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, FIN-00014, Finland
Elina Ikonen - Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, FIN-00014, Finland
Raimo Sulkava - Section of Geriatrics, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, FIN-70211, Finland
Michael Benatar - Neuromuscular Division, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Joanne Wuu - Clinical Translational Research Division, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Adriano Chiò - Department of Neuroscience, University of Turin, 10126 Turin, Italy
Gabriella Restagno - Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy
Giuseppe Borghero - Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, 09042 Cagliari, Italy
Mario Sabatelli - Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy
David Heckerman - Microsoft Research, Los Angeles, CA 90024, USA
Ekaterina Rogaeva - Tanz Centre for Research of Neurodegenerative Diseases and Toronto Western Hospital, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada
Lorne Zinman - Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
Jeffrey D Rothstein - Department of Neurology, Brain Sciences Institute, Johns Hopkins University, Baltimore, MD 21287, USA
Michael Sendtner - Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany
Carsten Drepper - Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany
Evan E Eichler - Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Can Alkan - Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Ziedulla Abdullaev - Chromosome Pathology Unit, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Svetlana D Pack - Chromosome Pathology Unit, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Amalia Dutra - Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
Evgenia Pak - Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
John Hardy - Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square House, London WC1N 3BG, UK
Andrew Singleton - Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Nigel M Williams - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Peter Heutink - Department of Clinical Genetics, Section of Medical Genomics, and Alzheimer Disease Center, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
Stuart Pickering-Brown - Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK
Huw R Morris - MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
Pentti J Tienari - Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, FIN-02900, Finland
Bryan J Traynor - Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
Publication Details: Neuron (Cambridge, Mass.), Vol.72(2), pp.257-268
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; UMMG Department of Neurology; UMMG Dept of Neurology - Neuromuscular Disorders Div
Language: English
Resource Type: Journal article
PMID: 21944779
PMCID: PMC3200438
Record Identifier: 991031577211802976